A leading disease incurred by women is breast cancer. Breast cancer is the second leading cause of death for women of all ages and the leading cause of death for women aged 25-55. Approximately one in eight women will incur breast cancer in their lifetimes. Approximately 220,000 surgeries are performed annually in the United States with almost 20 percent requiring the complete removal of the breast.
The current medical standard for determining breast cancer in women is mammography. For breast cancer detection, other than clinical examination and self-examination, women rely almost exclusively on mammography. It is estimated that more than 30 million mammograms are performed each year in the U.S. alone. Mammography is so insensitive that typically the average size of the tumor which can be detected is approximately 1.5 cm At that size, a tumor has probably been growing, undetected, for nearly 8 years on average. In fact, two-thirds of mammographically detected breast cancer is invasive. In addition, mammography is notorious for “false positive” readings, which lead to many unneeded biopsies. However mammography fails to detect up to 20% of breast cancers in women over 50 and up to 40% of breast cancers in younger women. Medical researchers have long recognized that nearly all breast cancer originates in the epithelial lining of the mammary duct system. Furthermore, it is well established that, in its early stages, most breast cancer develops very slowly and remains confined to the mammary ducts for up to 7-10 years. If these very early stages of premalignant and malignant disease could be detected and treated while within the mammary duct system, the result would be substantially better treatment outcomes: enhanced survivability, avoidance of chemotherapy and radiation, and breast conservation.
After detection breast cancer is generally treatable in three ways: surgery, radiation and chemotherapy. Surgery and radiation, of course, have risks and disadvantages well known to those skilled in the art. Chemotherapy may be disadvantageous as when the drugs involved cause sickness to the patient when they enter the blood stream.
Today's primary treatment of breast cancer is traditional surgery, either mastectomy or lumpectomy with radiation therapy. Surgery is, by definition, invasive and traumatic. Because the exact margins of cancerous growth are difficult to pinpoint, a surgeon may remove more breast tissue than is necessary or not remove enough. Between newly diagnosed breast cancer surgeries and re-excisions, approximately 180,000 lumpectomies are performed each year in the United States.
Mammary Intraductal Treatment (MIT) refers to a procedure in which abnormal cells in the lining of the mammary duct are destroyed to control abnormal intraductal pathology that may or may not be related to malignancy. Today, women with positive mammograms, positive biopsies or intraductal atypical (abnormal pathology) often have a choice of watchful waiting, medical therapy, or surgery (lumpectomy and mastectomy). The advancement of new technology and techniques for the treatment of breast disease has not kept pace with other medical areas, particularly in the area of minimally invasive techniques (mammary ductoscopy).
Benign conditions that can lead to abnormal intraductal assessment include intraductal papilloma, hyperplasia and atypical ductal hyperplasia and these can be removed without requiring invasive surgery. Likewise, hormonal therapies, and pharmaceutical agents (Tamoxifen) may control the growth of intraductal cancerous lesions. Intraductal treatment can be indicated for women who have not responded to medical therapy or choose not to take the agents due to side effects or other personal reasons. All women should have biopsies or intraductal samplings (lavage) to confirm the presence of atypical or malignant disease.
The present detection technique utilizes the mammary ductoscope allowing the physician to look directly into the mammary ducts to determine tissue fluorescense.
Attempts have been made to provide an instrument which will allow the taking of tissue samples within small duct areas. A simple double barrel catheter with adjacent lumens is disclosed in U.S. Pat. No. 6,221,622 with one of the lumens being used to irrigate the milk duct of a breast and the other lumen being used to aspirate the fluid which has entered the duct allowing a continuous flow of saline through the duct which hopefully carries enough cells and tissues for a biopsy. Problems in the use of such an instrument include the small size required by the narrow small diameter lumens which can be blocked or limit the flow of fluid back through the aspiration lumen and thus preclude significant tissue collection or cause duct collapse. While the '622 Patent shows a small lumen size, the size problem is magnified when the other existing prior art is attempted to be applied to breast ducts because of the small size and thin cell walls of the mammary ducts which can be ruptured.
Fluorescent substances in an organism are exemplified by NADH (nicotinamide adenine nucleotide), FMN (flavin mononucleotide) and pyridine nucleotide. The relationship between the intrinsic substances in an organism and the diseases has been clarified. If textures of an organism are irradiated with excitation light, fluorescent light having a wavelength longer than that of the excitation light is generated. Each of HpD (Hematoporphyrin), Photofrin and ALA (beta-aminolevulminic acid) has integrating characteristics into a cancer. By injecting any of the foregoing substances into an organism, irradiating the subject portion with excitation light and observing fluorescent light, a disease portion can be diagnosed and treated.
U.S. Pat. No. 4,556,057 discloses a system comprising a diagnosing laser beam source, a curing laser beam source and a normal photographing light source. The normal photographing light source is controlled in synchronization with the activation/deactivation of the diagnosing light source and fluorescent light generated due to irradiation with excitation light is captured by an image sensing apparatus having an image intensifier by a normal image sensing apparatus. The observed fluorescent image and observed normal image are displayed on monitors which correspond to the image sensing apparatuses so that a cancer can be diagnosed and cured.
I. Photodynamic Therapy
The destruction of the intraductal epithelial tissue can be performed by various energy delivering devices, namely, fluorescence.
It has been known for many years that photosensitizing compounds show a photochemical reaction when exposed to light. Photodynamic therapy (PDT) uses such photosensitizing compounds and lasers to produce tumor necrosis. Treatment of solid tumors by PDT usually involves the systemic administration of tumor localizing photosensitizing compounds and their subsequent activation by laser. Upon absorbing light of the appropriate wavelength the sensitizer is converted from a stable atomic structure to an excited state. Cytotoxicity and eventual tumor destruction are mediated by the interaction between the sensitizer and molecular oxygen within the treated tissue to generate cytotoxic singlet oxygen.
Two good general references pertaining to PDT, biomedical lasers and photosensitizing compounds, including light delivery and dosage parameters, are Photosensitizing Compounds: Their Chemistry, Biology and Clinical Use, published in 1989 by John Wiley and Sons Ltd., Chichester, U.K., ISBN 0 471 92308 7, and Photodynamic Therapy and Biomedical Lasers: Proceedings of the International Conference on Photodynamic Therapy and Medical Laser Applications, Milan, Jun. 24-271992, published by Elsevier Science Publishers B. V., Amsterdam, The Netherlands, ISBN 0 444 81430 2, both of which are incorporated herein by reference.
United States patents related to PDT include U.S. Pat. Nos. 5,095,030 and 5,283,225 to Levy et al.; U.S. Pat. No. 5,314,905 to Pandey et al.; U.S. Pat. No. 5,214,036 to Allison et al; and U.S. Pat. No. 5,258,453 to Kopecek et al., all of which are incorporated herein by reference. The Levy et al. patents disclose the use of photosensitizers affected by a wavelength of between 670-780 nm conjugated to tumor specific antibodies, such as receptor-specific ligands, immunoglobulins or immunospecific portions of immunoglobulins. The Pandey et al. patents are directed to pyropheophorbide compounds for use in standard photodynamic therapy. The Allison et al. patent is similar to the Levy patents in that green porphyrins are conjugated to lipocomplexes to increase the specificity of the porphyrio compounds for the targeted tumor cells. The Kopeck et al. patent also discloses compositions for treating cancerous tissues. These compositions consist of two drugs, an anti-cancer drug and a photoactivatable drug, attached to a copolymeric carrier. The compositions enter targeted cells by pinocytosis. The anti-cancer drug acts after the targeted cell has been invaded. After a period of time, a light source is used to activate the photosensitized substituent.
The potential for combining PDT with immunotherapy was explored by Krobelik, Krosl, Dougherty and Chaplin. See Photodynamic Therapy and Biomedical Lasers, supra, at pp. 518-520. In their study, they investigated a possibility of amplification of an immune reaction to PDT and its direction towards more pervasive destruction of treated tumors. The tumor, a squamous cell carcinoma SCCVII, was grown on female C3H mice. An immunoactivating agent SPG (a high molecular weight B-glucan that stimulates macrophages and lymphoid cells to become much more responsive to stimuli from cytokines and other immune signals) was administered intramuscularly in 7 daily doses either ending one day before PDT or commencing immediately after PDT. Photofrin based PDT was employed; photofrin having been administered intravenously 24 hours before the light treatment. The SPG immunotherapy was shown to enhance the direct killing effect of the PDT. The indirect killing effect (seen as a decrease in survival of tumor cells left in situ) was, however, much more pronounced in tumors of animal not receiving SPG. The difference in the effectiveness of SPG immunotherapy when performed before and after PDT suggested that maximal interaction is achieved when immune activation peaks at the time of the light delivery or immediately thereafter. With SPG starting after PDT (and attaining an optimal immune activation 5-7 days later), it is evidently too late for a beneficial reaction.
Photodynamic therapy (PDT) uses specifically designed drugs such as Foscan.RTM. (Scotia Pharmaceuticals), ALA (DUSA)and Photofiin (QLT Phototherapeutics) to destroy rapidly dividing cells. These drugs are selectively retained or generated at rapidly dividing cells and are subsequently excited by light to produce the desired effects. The primary mode of activity usually involves energy transfer from these photoexcited drugs to O2 to produce superoxides or O2 in its singlet state. To date this excitation has been provided by lasers, lamps, and new materials such as laser action in amplifying scattering media. Some of these sources are generally expensive and require complicated delivery systems.
Two of the most important photodynamic therapy drugs are the naturally occurring ALA compound and Photofrin. Both of these are porphyrin compounds that have a peak absorption at 630 nm with a line width of approximately 35 nm. Photofrin has recently received FDA approval for the treatment of esophageal cancer.
U.S. Pat. No. 5,087,636 to Jamieson, et al. discloses a method to identify and destroy malignant cells in mononuclear cell populations. This method includes the steps of contacting a composition of bone marrow cells or other cells with a green porphyrio of a specific compound, irradiating the cell composition with light at a wave length effective to excite fluorescence of the green porphyrio, and then detecting the presence or absence of fluorescence indicating malignancy. This reference also discloses the steps by which the bone marrow cells are removed, separated, washed and diluted to an appropriate concentration for treatment, incubated, centrifuged, and exposed to the irradiating light.
U.S. Pat. Nos. 5,308,608 and 5,149,708 to Dolphin, et al. disclose specific types of porphyrin compounds which may be used for detection, photosensitization, or the destruction of a targeted biological material when the targeted tissue is contacted with the specified porphyrin, and irradiated with light that excites the compound.
U.S. Pat. No. 5,211,938 to Kennedy, et al. discloses a method of detection of malignant and non-malignant lesions by photochemotherapy of protoporphyrin IX precursors. 5-aminolevulinic acid (5-ALA) is administered to the patient in an amount sufficient to induce synthesis of protoporphyrin IX in the lesions, followed by exposure of the treated lesion to a photo activating light in the range of 350-640 nanometers. Naturally occurring protoporphyrin IX is activatable by light which is in the incident red light range (600-700 nanometers) which more easily passes through human tissue as compared to light of other wave lengths which must be used with other types of porphyrins. The use of 5-ALA makes cell fluorescence easier to observe, and also greatly reduces the danger of accidental phototoxic skin reactions in the days following treatment since protoporphyrin IX precursors have a much shorter half life in normal tissues than other popularly used porphyrins.
Another set of prior art references exists which relate to flow cytometry utilizing fluorescence producing compounds. One such prior art reference includes U.S. Pat. No. 5,605,805 to Verwer, et al., which discloses a method for determining the lineage of acute leukemia cells in the sample by fluorocytometry. Other examples of fluorocytometry utilizing fluorescence include U.S. Pat. No. 5,418,169 to Crissman, et al., U.S. Pat. No. 5,556,764 to Sizto, et al., and U.S. Pat. No. 5,627,040 to Bierre.
Present methods relating to cancer screening using fluorescence detection systems require the use of interventional devices such as endoscopes which have the special capability of delivering specified light frequencies to a targeted area within a patient.
Accordingly, the tumor still needs to be sampled by an appropriate biopsy method. Generally, biopsy methods also require some type of sedation or anesthesia. Thus, traditional methods of confirming a malignancy may require at least two interventional surgical procedures.
Thus, there is a need in the art for new and better micro-cannula/endoscope assemblies and methods for using same that can be used to directly visualize the mammary ducts of a breast where visualization is by means of endoscopic devices, direct visualization and offers the additional advantage that the equipment required is comparatively simple to use and is less expensive than the equipment required to create photographic displays from such images. In addition, there is a need in the art for a method of ablating diseased or abnormal tissue which are located during such visualization within the mammary duct.